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Redox Signaling and Regional Heterogeneity of Endothelial Dysfunction in db/db Mice.

ABSTRACT: The variable nature of vascular dysfunction in diabetes is not well understood. We explored the functional adaptation of different arteries in db/db mice in relation to increased severity and duration of diabetes. We compared endothelium-dependent and -independent vasodilation in the aortae, as well as the carotid and femoral arteries, of db/db mice at three ages in parallel with increased body weight, oxidative stress, and deterioration of glycemic control. Vascular responses to in vitro generation of reactive oxygen species (ROS) and expression of superoxide dismutase (SOD) isoforms were assessed. There was a progressive impairment of endothelium-dependent and -independent vasorelaxation in the aortae of db/db mice. The carotid artery was resistant to the effects of in vivo and in vitro induced oxidative stress, and it maintained unaltered vasodilatory responses, likely because the carotid artery relaxed in response to ROS. The femoral artery was more reliant on dilation mediated by endothelium-dependent hyperpolarizing factor(s), which was reduced in db/db mice at the earliest age examined and did not deteriorate with age. Substantial heterogeneity exists between the three arteries in signaling pathways and protein expression of SODs under physiological and diabetic conditions. A better understanding of vascular heterogeneity will help develop novel therapeutic approaches for targeted vascular treatments, including blood vessel replacement.

SUBMITTER: Sallam NA

PROVIDER: S-EPMC7504187 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Redox Signaling and Regional Heterogeneity of Endothelial Dysfunction in db/db Mice.

Sallam Nada A NA Laher Ismail I

International journal of molecular sciences 20200826 17

The variable nature of vascular dysfunction in diabetes is not well understood. We explored the functional adaptation of different arteries in db/db mice in relation to increased severity and duration of diabetes. We compared endothelium-dependent and -independent vasodilation in the aortae, as well as the carotid and femoral arteries, of db/db mice at three ages in parallel with increased body weight, oxidative stress, and deterioration of glycemic control. Vascular responses to i ...[more]

PMID: 32858910

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Project description:Endothelial cell dysfunction and vessel stiffening are associated with a worsened prognosis in diabetic patients with cardiovascular diseases. The present study hypothesized that sex impacts endothelial dysfunction and structural changes in arteries from diabetic mice. In diabetic (db/db) and normoglycaemic (db/db+) mice, the mechanical properties were investigated in pressurized isolated left anterior descending coronary arteries and aorta segments that were subjected to tensile testing. Functional studies were performed on wire-mounted vascular segments. The male and female db/db mice were hyperglycaemic and had markedly increased body weight. In isolated aorta segments without the contribution of smooth muscle cells, load to rupture, viscoelasticity, and collagen content were decreased suggesting larger distensibility of the arterial wall in both male and female db/db mice. In male db/db aorta segments with smooth muscle cell contribution, lumen diameter was smaller and the passive stretch-tension curve was leftward-shifted, while they were unaltered in female db/db aorta segments versus control db/db+ mice. In contrast to female db/db mice, coronary arteries from male db/db mice had altered stress-strain relationships and increased distensibility. Transthoracic echocardiography revealed a dilated left ventricle with unaltered cardiac output, while aortic flow velocity was decreased in male db/db mice. Impairment of acetylcholine relaxation was aggravated in aorta from female db/db compared to control and male db/db mice, while impairment of sodium nitroprusside relaxations was only observed in aorta from male db/db mice. The remodeling in the coronary arteries and aorta suggests an adaptation of the arterial wall to the reduced flow velocity with sex-specific differences in the passive properties of aorta and coronary arteries. The findings of less distensible arteries and more pronounced endothelial dysfunction in female compared to male diabetic mice may have implications for the observed higher incidence of macrovascular complications in diabetic women.

Project description:Recent studies have demonstrated that hyperglycemia is a major risk factor for the development and exacerbation of cardiovascular disease (CVD). However, the molecular mechanisms involved in diabetic cardiomyopathy (DCM) have not been fully elucidated. In this study, we focused on the underlying mechanism of DCM. Leptin receptor-deficient db/db mice were used to model a type 2 diabetes mellitus (T2DM) model in our study. WT mice and db/db mice received 4-phenylbutyric acid (4-PBA) (25 mg/kg/day) and saline by intraperitoneal injection every other day for 4 weeks. WT and db/db mice were given tail vein injections of 100 μL of rAAV9-Sh-MAPK10 and rAAV9-Sh-GFP at the age of 6-8 weeks. Echocardiography was performed to measure cardiac function, histological examinations were used to evaluate ventricular hypertrophy and fibrosis. Quantitative RT-qPCR was used to assess the mRNA expression of Jun N-terminal kinase 3 (JNK3, MAPK10), atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and collagen I and III. Immunoblotting was performed to measure the levels of cardiac hypertrophy-related proteins, fibrosis-related proteins, endoplasmic reticulum stress (ERS)-related proteins and apoptosis-related proteins. TUNEL staining was performed to examine cardiomyocyte apoptosis. In contrast to 12-week-old db/db mice, 16-week-old db/db mice showed the most severe myocardial dysfunction. The DCM induced by hyperglycemia was largely alleviated by 4-PBA (25 mg/kg/day, intraperitoneal injection). Similarly, tail vein injection of rAAV9-Sh-MAPK10 reversed the phenotype of the heart in db/db mice including cardiac hypertrophy and apoptosis in db/db mice. The mechanistic findings suggested that hyperglycemia initiated the ERS response through the negative regulation of sirtuin 1 (SIRT1), leading to the occurrence of myocardial dysfunction, and specific knockdown of MAPK10 in the heart directly reversed myocardial dysfunction induced by hyperglycemia. We demonstrated that hyperglycemia promotes DCM in db/db mice through the ERS-MAPK10 signaling pathway in diabetic mice.

Dataset Information

Redox Signaling and Regional Heterogeneity of Endothelial Dysfunction in db/db Mice.

Publications

Redox Signaling and Regional Heterogeneity of Endothelial Dysfunction in <i>db/db</i> Mice.

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